Activation of the Endoperoxide Ascaridole Modulates Its Sensitizing Capacity

Abstract

The monoterpene ascaridole, a fairly stable endoperoxide found in essential oils such as tea tree oil can provoke allergic contact dermatitis which has been evidenced under patch test conditions. However, concomitantly we observed irritative skin reactions that demand further data underlining the sensitization potential of ascaridole. Here, we studied the effects of ascaridole on dendritic cell (DC) activation and protein reactivity, 2 key steps of chemical-induced skin sensitization. Treatment of human monocyte-derived DC with ascaridole found support for full DC maturation, a capability of sensitizers but not irritants. It induced significant upregulation of the expression of the costimulatory molecules CD86, CD80, CD40, and the adhesion molecule CD54 in a time-dependent manner. Maturation was accompanied by release of proinflammatory cytokines interleukin (IL)-1ß, tumor necrosis factor-α, IL-6, and IL-8. Similar to other chemical skin sensitizers including hydroperoxides, we observed a certain reactivity of ascaridole toward cysteine- but not lysine-containing peptides. During recent years, evidence accumulated for a radical mechanism as trigger for protein reactivity of peroxides. Treatment of the fairly stable endoperoxide ascaridole with iron as radical inducer ("activated ascaridole") resulted in cysteine peptide reactivity exceeding by far that of ascaridole itself. Furthermore, activated ascaridole showed increased potential for induction of the Nrf2 target gene heme oxygenase 1 and upregulation of CD86 and CD54 on THP-1 cells, an established DC surrogate. These results indicate that radical formation could be involved in the steps leading to skin sensitization induced by the endoperoxide ascaridole.

A phytochemical of modern medicinal perspective

“…From the result, it was found that maturation was accompanied by the release of proinflammatory cytokines, tumor necrosis factor-α, interleukin (IL)-6, IL-1β, and IL-8. Further radical formation may be involved in the skin sensitization [27].…”

Keratinocytes improve prediction of sensitization potential and potency of chemicals with THP-1 cells_suppl

“…the chemical's sensitization potency, is an essential value in quantitative risk assessment (Mackay et al, 2013). In vitro methods intended to reduce or replace animal testing in this area need to be able to predict hazard and also to categorize the potency of sensitizers.We and others have shown sensitizer-induced CD86 and CD54 upregulation on monocytic THP-1 cells as a model for DC activation (Bocchietto et al, 2007;Goebel et al, 2014;Krutz et al, 2015;Tietze and Blömeke, 2008;Yoshida et al, 2003). However, the impact of the presence of keratinocytes on the activation of THP-1 cells has not yet been fully investigated.…”

“…We and others have shown sensitizer-induced CD86 and CD54 upregulation on monocytic THP-1 cells as a model for DC activation (Bocchietto et al, 2007;Goebel et al, 2014;Krutz et al, 2015;Tietze and Blömeke, 2008;Yoshida et al, 2003). However, the impact of the presence of keratinocytes on the activation of THP-1 cells has not yet been fully investigated.…”

Understanding the skin sensitization capacity of ascaridole: a combined study of chemical reactivity and activation of the innate immune system (dendritic cells) in the epidermal environment

“…The finding that every positive reaction to oxidized-TTO was accompanied by a positive reaction to Asc supported the hypothesis that Asc might be a contact allergen in oxidized-TTO. Furthermore, we studied (Krutz at al. 2015) the capacity of Asc to react with proteins and evaluated its potential to mature monocyte-derived dendritic cell (DC), two key events of chemical-induced sensitization (OECD, 2012).…”